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Associative emotional learning, which is important for the social emotional functioning of individuals and is often impaired in psychiatric illnesses, is in part mediated by dopamine and glutamate pathways in the brain. The protein DARPP-32 is involved in the regulation of dopaminergic and glutaminergic signaling. Consequently, it has been suggested that the haplotypic variants of the gene PPP1R1B that encodes DARPP-32 are associated with working memory and emotion processing. We hypothesized that PPP1R1B should have a significant influence on the network of brain regions involved in associative emotional learning that are rich in DARPP-32, namely the striatum, prefrontal cortex (comprising the medial frontal gyrus and inferior frontal gyrus (IFG)), amygdala and parahippocampal gyrus (PHG). Dynamic causal models were applied to functional MRI data to investigate how brain connectivity during an associative emotional learning task is affected by different single-nucleotide polymorphisms (SNPs) of PPP1R1B: rs879606, rs907094 and rs3764352. Compared to heterozygotes, homozygotes with GTA alleles displayed increased intrinsic connectivity between the IFG and PHG, as well as increased excitability of the PHG for negative emotional stimuli. We have also elucidated the directionality of these genetic influences. Our data suggest that homozygotes with GTA alleles involve stronger functional connections between brain areas in order to maintain activation of these regions. Homozygotes might engage a greater degree of motivational learning and integration of information to perform the emotional learning task correctly. We conclude that PPP1R1B is associated with the neural network involved in associative emotional learning.

Variation of the gene coding for DARPP-32 (PPP1R1B) and brain connectivity during associative emotional learning